This Project has been at the center of this Program Project Grant since its inception in 1977. The objective continues to be an understanding of the mechanism by which cells sense cholesterol and adjust its uptake via the LDL receptor pathway and its synthesis via the cholesterol biosynthetic pathway so as to maintain an optimal level of cholesterol in cell membranes. An understanding of this control mechanism may help to explain why ingestion of cholesterol and saturated fatty acids leads to an elevation of LDL in plasma and the consequent atherosclerosis. In recent years, we have learned that an understanding of the SREBP pathway has another implication, equally as important as its implication for cholesterol homeostasis. This implication derives from the evidence that SREBPs regulate the synthesis of unsaturated fatty acids as well as cholesterol. These studies therefore may increase our understanding of the disordered fatty acid synthesis that predisposes to atherosclerosis in states of obesity, insulin resistance, and diabetes mellitus.